Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations

• Conformational-restriction was applied to the structure of DMABC(1).
• Ureas and thioureas were employed as carbamate bioisosteres.
• Cyclopropyl and pyrrolidine analogues confirmed 1-folded conformation bound to nAChRs.
• N-carbamoyl substitution determines selectivity for α4β2 nAChRs.

Exploration of small selective ligands for the nicotinic acetylcholine receptors (nAChRs) based on acetylcholine (ACh) has led to the development of potent agonists with clear preference for the α4β2 nAChR, the most prevalent nAChR subtype in the central nervous system. In this work we present the continuation of these efforts aimed at increasing this subtype selectivity by introduction of conformational restriction in the carbamoylcholine homologue, 3-(dimethylaminobutyl) dimethylcarbamate (DMABC). Our results highlight the importance of the N-carbamoyl substitution in α4β2-subtype selectivity. Moreover, we have confirmed the non-linear conformation of DMABC bound to nAChRs suggested by recent crystal structures of the compound in complex with the Lymnaea stagnalis ACh binding protein.

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